Sulphanilamido-aminopyridines and process for producing the same



. dissolve one or both substances.

Patented June 4, 1940 SULPHANILAMIDO-AMINOPYRIDINES AND PROCESS FORPRODUCING THE SAME Edmond T. Tisza, Bernard F. Duesel, and Harris L.Friedman, Yonkers, N. Y., assignors to Nepera Chemical 00., Inc., NeperaPark, N. Y., a corporation of New York No Drawing. Application August80, 1939, Serial No. 292,630

4 Claims.

Our invention relates to new substitution products of pyridine andrefers particularly to pyridine compounds having valuable therapeuticproperties and this application is a continuationin-part of the patentapplication for Sulphanil amido-amino-pyridines and process forproducing the same, filed in the United States Patent Ofilce .onNovember 29, 1938, under Serial Number 242,892.

. It is known that azo dyes prepared from diaminopyridines areveryimportant as urinary antiseptics, and further, sulphanilamide isalso known as an important therapeutic agent. We have found thatdiaminopyridines may be condensed with p-amino-benzene-sulphonamide toform new substances, which are valuable as therapeutic agents, and thatthey form starting materials for the production of other valuablecompounds as, for instance, they may be coupled with diazotised andtetrazotised amines of the arcmatic series.

The general formula of these compounds is:

The compounds are prepared by reactingp-acetamino-benzenesulphonylchloride with diamino-pyridines. One of theamino groups of the diaminopyridines is acetylated for protection, andby doing that the position of the condensation can be selected. In ourapplication Serial Number 242,892 we have shown that condensation takesplace, when the two substances are fused together'in a suitable vessel,and heated to the desired temperature. The condensation may be made alsoin a non-reacting solvent, like, for instance, benzene or chloroform.The solvent may After the condensation, the acetyl groups are hydrolyzedoff the usual manner.

The chemical reaction of the process following:

AcBN- NIL-i-ClSOz-GNHAO:

is the The hydrolyzation takes place in acid or alkaline solution,though experience shows that the alkaline solution is preferable.

Pyridine appears to be an exceedingly good solvent for the condensationas the hydrochloric acid formed in the first step is'taken up by the Isolvent and the yield is considerably increased.

EXAMPLE 1 20 grams pure 2-amino, 5-acetaminopyridine were dissolved in100 cc. dry pyridine and 32 grams p-acetamino benzene sulphonylchloridepurified by recrystallization out'of benzene were solved in 200 cc. 1%sodium hydroxide and boiled up with charcoal. 20 grams sodium hydroxidewere added to the filtered solution and refluxed for one hour tocomplete the hydrolysis. The solution was now neutralized to pH 7.0 andcooled on ice. The collected and washed precipitate was nowrecrystallized out of water with charcoal, and further purified byrecrystallization out of water.

The product so obtained,

LJMSOF N...

2-sulphanilamido, -5-aminopyridine forms pale pink colored needles. M.P. 157-9 C. It is slightly soluble in cold, more in hot water, alcohol,acetone, dilute alkalies and dilute acids, slightly soluble in ethylacetate. It is insoluble in chloroform, ether, benzeneand ligroine. Theforegoing formula was confirmed by analysis. In a nitrogen determination"(micro-Dumas) there was found N==20.93%. Theoretical N=21.20%.

ExAurLz 2 i 1 gram 2-amino, S-acetamino pyridine was condensed with 1.6g. p-acetaminobenzene-sulphonyichlorideas in Example 1 and the acetylderivative collected. The collected precipitate was suspended in 15 cos.hydrochloric acid of 10% and boiled gently for 20 minutes. All'went intosolution. After cooling, the solution was neutralized with sodiumbicarbonate, and the precipitate purified by recrystallization fromwater.

M. P. 158-159 C.

2-sulphanilamido, S-aminopyridine is a relatively nontoxic substance asexperiments on mice added. The mixture heated up considerably and tookon a deep red color.

prove. The table'below shows that 3 grams perkilogram are welltolerated.

Table I Oral acute toxicity of 2-suiphanilamido, li-aminopyrl- Numberdead,

time in days Percent deed

Dose in -l Number oi mice 4 3 0 Convulsons were produced at 4 grams perilogram OIOVUI see This new compound appears to be superior tosulphanilamide not only because of its low tox- Dose Percent survival,time Numper indays ber of Compoundused mouse mice in mgm. 1 2 3 4 6Sulphanilamide.-.- 10 100 76 15 0 50 2-sulphanilamido,

- o-aminopy'ridine. 10 100 92 76 44 30 25 Crmhm'l 0 icity but also byits therapeutic action. A comparative study has shown that the survivalof mice infected with streptococci and treated with our substances isfar greater than those treated with sulphanilamide, as can be seen fromthe following tables: Table II Stre tococci (Strain 1896) were used inthis experiment for in ecting the mice intra ritoneally and they. weretreated with 12 mg. of 2-sulp anilamido, fi-aminopyridine immediatelyafter infection, plus once daily for three consecutive days.

Dose Percent survival, time Numper g indays ber of Compound used mousemice in mgm. 1 2 3 4 ii 10 Sui hanilamide 12 100 80 20 2o 20 10 2-511phanilamido,

li-aminopyridlne. 12 -100 100 100 70 10 Control 0 Table III streptococci(Strain C203) were used in this experiment for infecting the mice.

aeoaeas These experiments establish the value of our compound fortherapeutic purposes.

We have shown in our co-pending application, Serial Number 242,892, thatazo dyes may be formed from our compound by coupling with diazotisedarylamines.

It is obvious that azo dyes and other compounds may be prepared from thecompound described in the foregoing specification without departing fromthe invention or sacrificing the advantages thereof; therefore, we donot intend to limit ourselves to the specific embodiment herein setforth except as indicated in the appended claims.

What we claim is:

1. The method of producing 2-sulphanilamido, S-aminopyridine comprisingreacting pacetamino-benzene-sulphony1 chloride with 2- amino,5-acetamino-pyridine, hydrolyzing oi! the acetyl groups by heating thereaction product in an acid or alkaline solution, neutralizing the thusproduced solution, removing the precipitate thus formed and purifyingthe thus formed precipitate.

2. The method of producing 2-sulphanilamido, 'S-aminopyridine comprisingreacting p-acetamino-benzene-sulphonyl chloride with 2-amino,S-acetamino-pyridine, hydrolyzing OK the acetyl groups by heating thereaction product in an alkaline solution, neutralizing the thus producedsolution, removing the precipitate thus formed and purifying the thusformed precipitate.

3. The method of producing 2-sulphaniiamido, 5-aminopyridine comprisingreacting p-acetamino-benzene-sulphonyl chloride with 2-amino,fi-acetamino-pyridine, hydrolyzing off the acetyl groups by heating thereaction product in an acid solution, neutralizing the thus producedsolution, removing the precipitate thus formed NHSOr-O-NH: N

and N-acyl derivatives thereof.

EDMOND 'r. TIBZA.

BERNARD F. DUESEL. HARRIS L. FRIEDMAN.

